Allene polyamines

ABSTRACT

NOVEL COMPOUNDS WHICH HAVE ACTIVITY IN INHIBITING THE CLOTTING OF BLOOD ARE SELECTED FROM BASES OF THE FORMULA   R3-(R4-)C=C=C(-R5)-C(-R6)(-R7)-CH2-NH-A   WHEREIN: (A) R3 IS HYDROGEN, (LOWER)ALKYL OR (LOWER)ALKENYL; (B) R4 IS (LOWER)ALKYL OR (LOWER)ALKENYL; (C) R3 AND R4 TAKEN TOGETHER WITH THE CARBON ATOM TO WHICH THEY ARE ATTACHED IS CYCLOALKYL OF 5 TO 7 RING CARBON ATOMS; (D) R5 IS HYDROGEN OR (LOWER)ALKYL; (E) EACH OF R6 AND R7 IS (LOWER)ALKYL, (LOWER)ALLKENYL, OR R6 AND R7 TOGETHER WITH CARBON ATOMS TO WHICH THEY ARE ATTACHED IS (I) CYCLOALKYL OF 5 TO 7 RING CARBON ATOMS; (II) CYCLOALKENYL OF 5 TO 7 RING CARBON ATOMS; OR (III) BICYCLOALKYL SELECTED FROM BORNYL, NORBORNYL OR NORBORNENYL; (F) A IS THE GROUP (I)   -X-N(-R1)-R2   WHEREIN X IS ALKYLENE OF 2 TO ABOUT 8 CARBON ATOMS AND SEPARATES THE ADJACENT NITROGEN ATOMS BY AN ALKYLENE CHAIN OF AT LEAST 2 CARBON ATOMS, MONOHYDROXY ALKYLENE OF 3 TO ABOUT 8 CARBON ATOMS, AND SEPARATES THE ADJACENT NITROGEN ATOMS BY AN ALKYLENE CHAIN OF AT LEAST 3 CARBON ATOMS, OR A CYCLOALKYLSUBSTITUTED ALKYLENE GROUP OF THE FORMULA   (-CH2)V-C(-(CH2)U-)-(CH2)V&#39;&#39;-   WHEREIN EACH OF V AND V&#39;&#39; IS AN INTEGER OF 0 TO 4, U WHEREIN EACH OF V AND V&#39;&#39; IS AN INTEGER OF 0 TO 4, U IS AN INTEGER OF 3 TO 5 PROVIDED THAT AT LEAST ONE OF V AND V&#39;&#39; IS 1, AND THE TOTAL OF V, V7 AND U IS NOT GREATER THAN 8, R1 IS HYDROGEN, (LOWER)ALKYL, PHENYL, HYDROXY(LOWER)ALKYL, CYCLOALKYL OF 4 TO 6 RING CARBON ATOMS, DI(LOWER)ALKYLAMINO(LOWER)ALKYL, PYRIDYL(LOWER)ALKYL, PIPERIDYL(LOWER)ALKYLAMINO(LOWER) ALKYL, OR PIPERIDYL(LOWER)ALKYL, R2 IS HYDROGEN, (LOWER)ALKYL OR HYDROXY(LOWER)ALKYL, OR R1 AND R2 TAKEN TOGETHER WITH THE NITROGEN TO WHICH THEY ARE ATTACHED IS PIPERAZINO, N-(LOWER)ALKYLPIPERAZINO, MORPHOLINO, PYRROLIDINO, AZIRIDINO, PIPERIDINO, (LOWER)ALKYLPIPERIDINO, (LOWER)ALKYLIMIDAZOLIDINO, OR (II) A IS   -(CH2)N-CH&lt;(-CH2-CH(-R9)N-N(-R8)-(CH2)M-)   WHEREIN N&#39;&#39; IS AN INTEGER OF 0 TO 3, M IS AN INTEGER OF 1 OR 2, R8 IS HYDROGEN, (LOWER)ALKYL, (LOWER) ALKENYL, HYDROXY(LOWER)ALKYL, PHENYL(LOWER)ALKYL, CYANO(LOWER)ALKYL, PIPERIDINO(LOWER)ALKYL, R9 IS (LOWER)ALKYL; AND N IS IN INTEGER OF 0 TO 4; OR PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS OF SAID BASES.

United States Patent '0 3,712,896 ALLENE POLYAMINES Charles H. Tilford, Atlanta, Ga., and Thomas R. Blohm and Robert D. McKenzie, Cincinnati, Ohio, assignors to Richardson-Merrell Inc., New York, N.Y.

No Drawing. Original application Apr. 1, 1969, Ser. No. 812,408, now Patent No. 3,641,155. Divided and this application Feb. 25, 1971, Ser. No. 119,026

Int. Cl. C07d 29/28 US. Cl. 260--293.87 16 Claims ABSTRACT OF THE DISCLOSURE Novel compounds which have activity in inhibiting the clotting of blood are selected from bases of the formula (A) R is hydrogen, (lower)alkyl or (lower)alkenyl;

(B) R is (lower)alkyl or (lower)alkenyl;

(C) R and R taken together with the carbon atom to which they are attached is cycloalkyl of 5 to 7 ring carbon atoms;

(D) R is hydrogen or (lower) alkyl;

(E) each of R and R is (lower)alkyl, (lower)a1kenyl, or R and R together with the carbon atom to which they are attached is (i) cycloalkyl of 5 to 7 ring carbon atoms; (ii) cycloalkenyl of 5 to 7 ring carbon atoms; or (iii) bicycloalkyl selected from bornyl, norbornyl or norbornenyl;

(F) A is the group (i) wherein X is alkylene of 2 to about 8 carbon atoms and separates the adjacent nitrogen atoms by an alkylene chain of at least 2 carbon atoms, monohydroxy alkylene of 3 to about 8 carbon atoms, and separates the adjacent nitrogen atoms by an alkylene chain of at least 3 carbon atoms, or a cycloalkylsubstituted alkylene group of the formula wherein each of v and v' is an integer of to 4, a is an integer of 3 to provided that at least one of v and v is 1, and the total of v, v and ,u is not greater than 8, R is hydrogen, (lower)alkyl, phenyl, hydroxy(lower)alkyl, cycloalkyl of 4 to 6 ring carbon atoms, di(1ower)alkylamino(lower)alkyl, pyridyl(lower)a1kyl, piperidyl( lower) alkylamino lower) alkyl, or piperidyl(lower)alkyl, R is hydrogen, (lower)alkyl or hydroxy(lower)alkyl, or R and R taken together with the nitrogen to which they are attached is piperazino, N-(lower)alkylpiperazino, morpholino, pyrrolidino, aziridino, piperidino, (low- (lower)alkylirnidazolidino,

er) alkylpiperidino, or

(ii) A is This application is a division of application Ser. No. 812,408, filed Apr. 1, 1969 and now US. Pat. No. 3,641,- 155.

This invention relates to novel allene polyamine compounds and processes for their preparation. More particularly, this invention relates to allene polyamine bases of the formula 4 1 Formula I wherein:

(A) R is hydrogen, (lower)alkyl or (lower)alkeny1;

(B) R, is (lower)alkyl or (lower)alkenyl;

(C) R and R taken together with the carbon atom to which they are attached is cycloalkyl of 5 to 7 ring carbon atoms;

(D) R is hydrogen or (lower)alkyl;

(E) each of R and R is (1ower)alkyl, (lower)alkenyl, or R and R" together with the carbon atom to which they are attached is (i) cycloalkyl of 5 to 7 ring carbon atoms;

(ii) cycloalkenyl of 5 to 7 ring carbon atoms; or (iii) bicycloalkyl selected from bornyl, norbornyl or norbornenyl;

(F) A is the group (i) wherein X is alkylene of 2 to about 8 carbon atoms and separates the adjacent nitrogen. atoms by an alkylene chain of at least 2 carbon atoms, monohydroxy alkylene of 3 to about 8 carbon atoms, and separates the adjacent nitrogen atoms by an alkylene chain of at least 3 carbon atoms, or a cycloalkyl-substituted alkylene group of the formula wherein each of v and v is an integer of 0 to 4, a is an integer of 3 to 5 provided that at least one of v and v' is 1, and the total of v, v' and ,u. is not greater than 8, R is hydrogen, (lower)a1kyl, phenyl, hydroxy(lower)alkyl, cycloalkyl of 4 to 6 ring carbon atoms, di(lower)alkylamino (lower)alkyl, pyridyl- (lower) alkyl, piperidyl (lower) alkylamino (lower) alkyl, or piperidyl(lower)alkyl, R is hydrogen, (low- 3 er) alkyl or hydroxy(lower)alkyl, or R and R taken together with the nitrogen to which they are attached is piperazino, N-(lower)alkylpiperazino, morpholino, pyrrolidino, aziridino, piperidino, (lower)alkylpiperidino, (lower)alkylimidazolidino, or (ii) A is wherein n' is an integer of to 3, m is an integer of 1 or 2, R is hydrogen, (lower)alkyl, (lower)alkenyl, hydroxy(lower)alkyl, phenyl(lower)alkyl, cyano- 1ower)alkyl, piperidino(lower)alkyl, R is (lower) akyl; and n is an integer of 0 to 4;

and pharmacologically acceptable acid addition salts of such base form of the compounds. The compounds of this invention inhibit the clotting of blood when administered to animals.

In the above Formula I, R can be hydrogen, (lower) alkyl or (lower)alkenyl. R can be (lower)alkyl or (lower)alkenyl. Preferably, both R and R are (lower)alkyl. Apart from each R and R being a separate group, R and R taken together with the carbon atom to which they are attached, can be cycloalkyl of to 7 ring carbon atoms. Illustrative of such cycloalkyls and other cycloalkyl groups in the compounds of this invention wherein the cycloalkyl has 5 to 7 ring carbon atoms, there can be mentioned cyclopentyl, cyclohexyl and cycloheptyl.

The term (lower) as used herein to describe alkyl or hydroxyalkyl relates to alkyl or hydroxyalkyl groups having from 1 to 6 carbon atoms. Such groups can be straight chained or branched chained. Illustrative of (lower)alkyls as can be represented by various designators, e.g., R in the formulas of compounds of this invention, there can be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, isoamyl, n-pentyl, n-hexyl and the like. Illustrative of (lower)hydroxyalkyl there can be mentioned: Z-hydroxyethyl, 2- and 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxy-1,l-dimethylethyl, hydroxypentyl, hydroxyhexyl and the like.

The term (lower) as used herein to describe alkenyl relates to alkenyl having from 3 to 6 carbon atoms. Illustrative of (lower)alkenyl groups as can be represented by various designators in formulas of the compounds of this invention, there can be mentioned: allyl, 3-butenyl, 2-pentenyl, 4-hexenyl and the like.

R in the above Formula I can be hydrogen or (lower) alkyl. Preferably, R is hydrogen.

Each of R and R in Formula I can be (lower)alkyl or (lower)alkenyl. As (lower)alkyls or (lower)alkenyls, each of the R and R groups can be the same or different. Additionally, R and R together with the carbon atom to which they are attached can be cycloalkyl or cycloalkenyl of 5 to 7 carbon atoms, e.g., cyclohexyl, cyclohex-3-enyl, or bicycloalkyl such as norbornenyl, norbornyl or bornyl. Preferably, each of R and R is (lower(alkyl and particularly (lower)alkyl of about 2 to 4 carbon atoms.

It can be seen from the previous description of the above Formula I that the designator A can be (i) the group R1 --XN or (ii) the group These groups will be described more fully hereinbelow. Preferably, such group is When A is the group (n') can be an integer of O to 3 and preferably 1 to 3; (m) is an integer of l to 2, R is (lower)alkyl, (n) is an integer of 0 to 4 and preferably 0, and R is hydrogen, (lower)alkyl, (lower)alkenyl, hydroxy(lower)alkyl, preferably of 1 to 3 carbon atoms, phenyl(lower)alkyl, cyano(lower)alkyl, or piperidino(lower)alkyl). Preferably the phenyl(lower)alkyl, cyano(lower)alkyl and the piperidino(lower)alkyl have from 1 to 3 carbon atoms in the alkyl group. The hydrogen in the ring simply denotes a saturated ring such as that of piperidyl or pyrrolidyl, which can be attached to the (CH group or directly to the adjacent secondary amine through any of the ring carbon atoms of said saturated cyclic group. Preferred bases of such compounds can be represented by the following formula:

Formula II wherein each of R R R and R is (lower)alkyl, (n') is an integer of 1 to 3, (m) is an integer of 1 or 2, and R is hydrogen, (lower)alkyl, (lower)alkenyl, hydroxy- (lower)alkyl of 1 to 3 carbon atoms, phenyl(lower)alkyl having 1 to 3 carbon atoms in the alkyl group, cyano- (lower)alkyl having 1 to 3 carbon carbon atoms in the alkyl group, or piperidino(lower)alkyl having 1 to 3 carbon atoms in the alkyl group; or pharmaceutically acceptable acid addition salts of said bases.

As shown by the above Formula I, A can also be an amino or polyamino group as represented by The designator X can be: straight or branched chain alkylene having from 2 to 8 carbon atoms which separates the above shown amino nitrogen from the adjacent nitrogen, i.e., that in the NH group of Formula I by an alkylene chain of at least 2 carbon atoms, e.g., ethylene (-CH -CH and preferably straight chain alkylene of 2 to 4 carbon atoms; straight or branched chain monohydroxy-substituted alkylene which separates the adjacent nitrogen atoms by an alkylene chain of at least 3 carbon atoms; or a cycloalkyl-substituted alkylene as described hereinbefore. As stated hereinabove, the alkylene or hydroxyalkylene separates the two nitrogen atoms, i.e., that adjacent to A in Formula I from the group, by an alkylene chain of at least 2 carbon atoms in the case of alkylene and at least 3 carbon atoms in the case of hydroxyalkyleue. Thus, these two nitrogens are not attached to the same carbon atom, X is preferably alkylene of 2 to 6 carbon atoms. When X in the is alkylene and each of the R and R groups is (lower) alkyl, such group is also referred to herein simply as di (lower)alkylaminoal'kyl. Preferred compounds containing the group are those which can be represented in the base form by the formula wherein: each of R R, R and R is (lower)alkyl; X is alkylene of 2 to 6 carbon atoms and separates its adjacent nitrogen atoms by an alkylene chainof at least 2 carbon atoms; R is hydrogen, (lower)alkyl, phenyl, hydroxy(lower)alkyl, cycloalkyl of 5 t 7 ring carbon atoms, di(lower)alkylamino(lower)alkyl, pyridyl(lower) alkyl, piperidyl(lower)alkylamino(lower)alkyl, or piperidyl(lower)alkyl; R is hydrogen, (lower)alkyl, or hydroxy(lower)alkyl; or R and R together with the nitrogen to which they are attached is piperazino, N-(1ower) alkylpiperazino, morpholino, pyrrolidino, aziridino, piperidino, (lower)alkylpiperidino or (lower)alkylimidazolidino. In the various groups for R having an alkyl bridging group between a heterocyclic ring and the nitrogen of an amino group or between two amino groups, such alkyl is preferably (lower)alkyl of 1 to 3 carbon atoms and the heterocyclic ring, e.g., pyridyl, piperidyl, can be attached to such (lower)alkyl of 1 to 3 carbon atoms through any carbon atom of the heterocyclic ring. One of the nitrogens of an amino group referred to in the above sentence can be the nitrogen to which R is attached.

The novel compounds of this invention can be prepared by various methods. By one method, an allene aldehyde is allowed to react with a polyamine to obtain an imine condensation intermediate product. The imine unsaturation of such product is then reduced to obtain compounds of this invention. The chemical equations of this procedure are shown below under Method A. The allene aldehyde reactants are known compounds or can be prepared by conventional procedures. United States Pat. 3,225,102, which issued on Dec. 21, 1965, shows suitable allene aldehyde reactants. Further, Example 3 herein shows the preparation of such allene aldehydes by certain techniques, whereas Table I shows properties of additional allene aldehydes prepared by the process employed in Example 3 herein.

Alternatively, the compounds can be prepared by the reaction of an allene aldehyde with hydroxylamine in order to obtain a hydroxylimine thereof which is subsequently reduced to the corresponding amine and then reacted with an amine aldehyde simultaneously with rednction or followed by reduction of the imine. The chemical equations for this procedure are shown below under Method B. In the following Methods A and B, the various groups, e.g., R R R R", R and A, have the same meanings as those given hereinbefore, whereas KBH, represents potassium borohydride and LAH represents lithium aluminum hydride.

In the above Method A, the molar ratio of allene aldehyde to polyamine reactant can vary over a wide range such as that of about 0.5 to 2 moles of the polyamine per mole of the allene aldehyde. Preferably, however, the allene aldehyde and polyamine are used in equimolar ratios. The reaction is effected by contacting the allene aldehyde with the polyamine, preferably in an inert organic solvent, and heating the reaction mixture. Illustrative of inert organic solvents which can be used there can be mentioned various hydrocarbons such as toluene, benzene or xylene; and alcohols, e.g., methanol, ethanol, and the like. The temperature at which the reaction mixture is heated can vary over a wide range such as that of a temperature of about 65 C. to 140 C. The heating is advantageously effected by refluxing the reactants in the inert solvent. During the condensation reaction, the theoretical amount of water is preferably removed from the reaction mixture. The reaction time can vary over a wide range, and usually from about one-half to about 3 hours, although for convenience the mixture can reflux overnight or longer.

The intermediate imine of the Method A procedure can be isolated and purified if desired, or the solvent can simply be removed, for example, by distillation or evaporation and then the imine reduced, to eliminate the imine unsaturation, with a reducing agent such as sodium or potassium borohydride. The quantity of such borohydride cannot vary over a wide range, but it is generally in excess of the theoretical amount necessary for the reduction, for example, from about 2 to 25 moles of the borohydride per mole of the amine. The borohydride reducing agent is preferably used together with an organic solvent such as methanol. The quantity of such solvent can vary over a wide range such as about ml. for each tenth mole of each reactant, although this can vary over a wide range such as about 50 to 200 ml. of the solvent per tenth mole of each reactant. In place of methanol, other solvents can be used such as other (lower)alkanols, e.g., ethanol. However, when other alkanols are used, it is preferred that the reaction mixture be warmed to about 40 C. to 50 C. after the amine addition. This increases the solubility of the borohydride and hastens the reaction.

In the usual procedure for reduction of the imine unsaturation, the imine is added to a cooled, for example, about C. to C., stirred mixture of potassium borohydride (KBH in methanol over a short period, e.g., 15 to 90 minutes, and preferably about minutes. The mixture is then permitted to stand until completion of the reaction, e.g., from 2 hours to 3 days or more. After completion of the reaction, the solvent, for example, methanol, can be removed by evaporation. Water is then added to the reaction mixture to decompose the residue. The amount of water added is not critical and can vary over a wide range such as that of about 15 to 50 moles of water per mole of starting imine material, but preferably about to moles of water per mole of starting imine material. The final product of this Method A can be recovered from the reaction mixture by conventional techniques. Illustrative of such techniques there can be mentioned solvent extraction, for example, with naphtha, benzene, toluene, and the like.

In the Method B for preparation of the compounds of this invention, an allene hydroxylamine is prepared from an allene aldehyde and hydroxylamine. The allene hydroxylamine is then reduced, for example, with lithium aluminum hydride to obtain the primary amino compound which can be reacted with an amine aldehyde in the presence of potassium or sodium borohydride to obtain the compounds of this invention. This method is specifically illustrated in Examples 8-10.

Some of the compounds of this invention can be resolved to their d and l optical isomers.

The pharmacologically acceptable acid addition salts of the novel base compounds of this invention can be those of inorganic or organic acids. Illustrative of inorganic acids there can be mentioned: hydrochloric acid; hydrobromic acid; sulfuric acid; phosphoric acid; and the like. Illustrative of organic acids there can be mentioned: lactic acid; pyruvic acid; malonic acid; succinic acid; maleic acid; tartaric acid; malic acid; citric acid; and the like.

The novel compounds of this invention are anticoagulants. They have been found to prolong clotting time of blood when administered orally or parenterally to rats and to inhibit platelet aggregation such as that induced by the addition of adenosine diphosphate when added to samples of platelet-rich plasma. This is a new type of anticoagulant mechanism and is quite dilferent from both heparin and dicumarol type anticoagulants. Heparin has an effect on blood coagulation both in vivo and in vitro due to its inhibition of the enzyme thrombin and fibrin clot formation. The dicumarol type affects the level of the proenzyme, prothrombin, in the blood by inhibiting its synthesis in the liver and is therefore effective only in vivo. The compounds of this invention have an effect on platelet function. This effect is found in vivo and in vitro. These anticoagulants can find particular utility in the treatment, of thrombotic disease, especially of the arterial system, e.g., to inhibit thrombosis of coronary and cerebral arteries, where heparin and dicumarol type anticoagulants do not completely protect against formation of a thrombus. The compounds of this invention can be administered to animals, e.g., mammals such as rats or dogs, over a Wide dosage range, e.g., daily doses from about 1 to 100 milligrams (mg.) per kilogram ('kg.) of animal body weight and ordinarily from about 10 to 30 mg./kg. of animal body weight per day by oral route or somewhat less when administered parenterally. These'anticoagulants can be administered in unit dosage form, e.g., in tablets, capsules or ampoules, together with a significant quantity of a pharmaceutical carrier containing from about to 500 milligrams of the anticoagulant. These anticoagulants generally show little, and in some cases, an absence of hypotensive activity.

The following examples are illustrative of the invention.

EXAMPLE 1 Preparation of 2-butyl-N-(3-diethylaminopropyl)-2- ethyl-5-methyl-3,4-hexadienylamine A mixture of 26 g. of 3-diethylaminopropylamine, 39 g. of 2-butyl 2 ethyl 5 methyl 3,4 hexadienal, and 200 ml. of toluene was refluxed with an attached water-trap. After several hours, 3.5 ml. (98% oftheory) of water had collected. The mixture Was subjected to distillation using a rotary evaporator and the steam bath as the source of heat. The oily residue was added to a stirred mixture of 16 g. of potassium borohydride in 200 ml. of methanol with ice bath cooling; the time of addition was approximately a half hour. The mixture was stirred overnight (16-18 hours) and a clear solution resulted. It was rotary evaporated on the steam bath. To the viscous semi-solid residue was added 150 ml. of water with stirring. The oil that separated was extracted With about 150 ml. of naphtha and fractionally distilled. The subject compound was in the form of a colorless oil which distilled at 119-121 (0.28 mm.) and amounted to 42 g., 11 1.4695. Infrared spectra were in agreement with the structure. This is Compound No. 14 of Table II.

EXAMPLE 2 Preparation of 1-[1-(2-butyl-2-ethyl-S-methyl-S,4- hexadienylaminomethyl cyclohexyl piperidine The intermediate 1 piperidinocyclohexylmethylamine was prepared as follows. To a stirred mixture of 8 g. of lithium aluminum hydride in 280 ml. of tetrahydrof-uran (dried over 5 molecular sieves) was added 28 g. of commercial 1 piperidinocyclohexanecarboxarnide in 5-7 g. portions with ice bath cooling. The mixture was stirred overnight at room temperature and decomposed with 30 ml. of a saturated sodium potassium tartarate solution. The mixture Was filtered and the filtrate was fractionally distilled at -90 (0.5 mm.) to yield 18 g. of crude product. Infrared spectra indicated a small amount of unchanged starting carboxamide present.

A mixture of the above prepared base (18 g.), 21 ml. of Z-butyl 2 ethyl 5 methyl 3,4 hexadienal and 100 ml. of toluene was then processed in the same manner as in Example 1. The yield of the subject compound as a colorless oil distilling at 1547 (0.15 mm.) was 22 g. This is Compound No. 37 of Table III.

A sample of the subject compound was dissolved in ether and alcoholic hydrogen chloride was added with cooling till the mixture was acid to congo red indicator paper. An oil precipitated that crystallized overnight at 5. This dihydrochloride salt of the subject compound was recrystallized from acetone-ether. M.P. 184-6" dec.

EXAMPLE 3 Preparation of N- (2-aziridinoethyl -2-butyl-2-ethyl-5- methyl-3,4-hexadienylamine When the procedure in Example 1 was followed with N-(Z-aminoethyl)aziridine, some imine intermediate was a substantial contaminant as shown by infrared. The procedure was repeated using 85 g. of N-(Z-aminoethyl) aziridine, 230 ml. of 2-butyl-2-ethyl-5-methyl-3,4-hexadienal and 1 liter of toluene. After a few hours refluxing the theoretical amount (18 ml.) of water was collected. The reaction mixture was rotary evaporated, and the residue was added to 80 g. of potassium borohydride suspended in 1 liter of methanol with cooling. This time the mixture was stirred under reflux for 18-20 hours, and worked up as in Example 1. The desired product was collected as an oil distilling at -8" ,(0.45 mm.) and amounted to 109 g. Infrared analysis confirmed the presence of the functional groups with little or no C=N stretch. This is Compound No. 29 of Table III.

EXAMPLE 4 Preparation of 4 [2 (2-[Z-butyl-Z-ethyI-S-methyl-3,4- hexadienylamino] ethylamino ethylaminomethyl] piperdine A solution of 13 g. of the above aziridine (Example 3), 11 g. of 4aminoethylpiperidine, and 100 ml. of toluene was refluxed two days and distilled. The product, as a colorless oil distilling at 182-4 (0.2 mm.), amounted to 5.5 g. Infrared analysis showed the C=C=C group was present.

Analysis.-Calcd (percent): C, 72.96; H, 12.25; N, 14.79. Found (percent): C, 72.72; H, 12.51; N, 14.80.

EXAMPLE 5 Preparation of N-(2-butyl-2-ethyl-5-methy1-3,4-hexadienyl -1-methyl-2-pyrrolidineethylamine The procedure in Example 1 was followed using 5 g. (0.04 mole) 2-(2-aminoethyl)-1-methylpyrrolidine, 9 ml. (0.04 mole) of 2-butyl-2-ethyI-5-methyl-3,4-hexadienal, and 40 ml. of toluene. The desired product after potassium borohydride reduction distilled at l22-5/0.2 mm.; yield 8 g. This is Compound No. 31 of Table III.

EXAMPLE 6 Preparation of N-(Z-butyl-Z-ethyl-5-methyl-3,4-hexadienyl)-1-pyrrolidineethylamine The procedure of Example 1 was followed with 23 g. (0.2 mole) of N-(2-aminoethyl)pyrrolidine, 46 ml. (0.2 mole) of 2-butyl-2-ethyl-S-methyl-3,4-hexadienal, and 200 ml. toluene. At 125-6/ 0.3 mm., 39 g. of desired product was collected as a colorless oil. This is Compound No. 28 in Table III.

EXAMPLE 7 Preparation of 2-butyI-Z-ethyI-S-methyLN-(1-methyl-4- piperi-dylmethyl) -3,4-hexadienylamine A mixture of 4 g. 0.03 mole) 4-aminomethyl-N-methylpiperidine, 7 g. (0.03 mole) of 2-butyl-2-ethyl-5-methyl- 3,4-hexadienal, ml. of toluene was refluxed as in Exam- 20 ple 1. After reduction by potassium borohydride, 6 g. of

TABLE I Analysis 3.1. Cale. Found Molecular No. R R R R R O. Mm. formula C H C H 1 CH2=CHCH2CH2- CH H CaHa C4110 96-9 0.15 CwHzsO 82.00 11.18 82.51 10.99

2 CH; CHa H RR O -8 .20 012E100 81.77 9.15 81.55 9.26

3 CH; CH H? 116-8 0.30 0 111100 82.93 8.57 83.01 8.65

4 R R C H C211 C4Hn 96-9 0.10 0 5E260 81.99 11.18 82.08 11.10

5 H RR C 96 0.15 015E200 83.28 9.32 83.28 9.40

1 7 1 8 ensues aaaaaaaa e w of v and an w of to 4. GREGATION CAUSED BY ADENOSINE DIPHOSPHATE M 18 all Integer 0f 3 t0 5 pro'vlded that at least IN PLATELET'RICH HUMAN PLASMA one of v and v is 1, and that the total of v, v' Percent Percent and ,u. is not greater than 8; R is pyridyl(lower a... teanag-a 0...- ii-$252 area: 5 Piperidywoww alkylamino flower) Po n Ina/m1: aggl'opound m ./m1f aggrealkyl or piperidyl(lower)alkyl; and R is hydro- Noplasma gation No. plasma gation gen, (lower)alkyl, or hydroxy(lower)alkyl, or 100 0 R and R taken together with the nitrogen atom 8 igg to which they are attached is piperazino, 100 7 10 N-(lower)alkylpiperazino, morpholino, pyrroliigg dino, aziridino, piperidino, (lower)alkylpiperi- 100 100 dino, or (lower)alkylamidazolidino, or a 12% i355 13%) 15 {(1a) 1 a 0R). as is u Ham-HE 100 100 3% 3 wherein n is an integer of 0 to 3; m is an inte- 100 1 ger of 1 or 2; R is hydrogen, (lower)alkyl, 18% 188 0 (lower)alkenyl, hydroxyflower) alky'l, phenyl- 100 100 (1ower)alkyl, cyano(lower)alkyl, or piperidinogg 2g (lower)al kyl; R is (lower)a1kyl; and n is an 100 100 integer of 0 to 4; igg or a pharmaceutically acceptable acid addition salt of said base.

2. A compound of claim 1 wherein R is hydrogen.

Clotting time (in seconds)iS.E.

Time after compound administration Compound Dose, No. in N0. Route rug/kg. group Control 1hr. Zhrs. hrs. 5hrs.

Control P.0. l 6 3705524 4205:15 430i8 14 8.0. 6 400:|:l0 410113 580:l;49 R0. 30 6 39512 6105181 s95=r=77 1 Llsotonie saline. 1 P value 05. 3 P value .02. 4 P value .00l.

What is claimed is: 3. A compound of claim 1 wherein R is hydrogen; 1. A compound selected from a base of the formula A is R3 R5 R0 C=C=JJ-JJ-CHz-NHA R4/ 1 wherein: each of R R R and R is (lower)alkyl; n is an integer R3 hydrogen (lowanalkyl or (loweflalkenyl; of 1 to 3; m is an integer of 1 or 2; and R is hyrogen, R4 13 (lovzioalkyl or (lowerhlkenyh (lower)alkyl, (lower)alkenyl, hydroxy(lower)alkyl, phen- R3 aT 1d R taken together wlth carbcn y1(lower)alky1, cyano(lower)alkyl or piperdinotlower) WhlCh they are attached 1s cycloalkyl of 5 to 7 ring alkYL f atoms; 50 4. A compound of claim 3 wherein m is 2. R5 15 hydrogen (loweflalkyk 5. A compound of claim 4 wherein R is hydrogen. each of R6 and R7 15 (loweflalkyl; (lowenalkenyl, or 6. A compound of claim 4wherein R is Phenyl-(lower) R6 and togethefr with the carbon to which alkyl having from 1 to 3 carbon atoms in said (lower)- they are attached is cyoloalkyl of 5 to 7 ring carbon alkyl group atoms, cycloalkenyl of 5 to 7 ring carbon atoms, A compound of claim 4 wherein R8 is hydmmh or bicycloalltyl selected from bornyl, norbornyl or (loweUalkYL A lilgrbomenyl; and A compound of claim 4 wherein R is (lower)alkn the group 6 A compound of claim 1 wherein each of R R". R

R and R is lower alkyl; R is hydrogen; A is --X-N/ R1 R2 --XN/ wherein X is alkylene of 2 to about 8 carbon atoms and separates the adjacent nitrogen atoms wherein X is alkylene of 2 to 6 carbon atoms; R is pynby an alkylene chain of at least 2 carbon atoms, dyl(lower)alkyl, piperidylflower) alkylamino(lower)alkyl, monohydroxy alkylene of 3 to about 8 a bo or piperidyl(lower)alkyl; R is hydrogen, (lower)alkyl or atoms and separates the adjacent nitrogen atoms hydroxy(lower)alkyl; or R and R together with the nitroby an alkylene chain of at least 3 carbon atoms, gen to which they are attached is piperazino, N-(lower) or a cycloalkyl-substituted alkylene group of alkylpiperazino, morpholino, pyrrolidino, aziridino, piperof the formula idino, (lower)alkylpipcridino or (lower)alkylimidazolidino. C 10. A compound of claim 9 wherein R is hydrogen and T 2 v C D R is pyridyl(lower)alkyl having from 1 to 3 carbon atoms (0112)" in said (lower)alkyl group.

11. A compound of claim 9 wherein R is hydrogen and R is piperidyl(lower)'alkyl having from 1 to 3 carbon atoms in said (lower)alkyl group.

12. A compound of claim 9 wherein R and R together with the nitrogen atom to which they are attached is piperazino, N-(lower)alkylpiperazino, morpholino, pyrrolidino, aziridino, piperidino, (lower)alkylpiperidino or (lower) alkylimidazolidino.

13. A compound of claim 12 wherein R and R together with the nitrogen atom to which they are attached is 2-methy1imidazolidino.

14. A compound of claim 1 wherein R is methyl, R is methyl, R is hydrogen, R is ethyl, R is butyl and A 15. A compound of claim 1 wherein R is methyl, R is methyl, R is hydrogen, R is ethyl, R is butyl and A is 16. A compound of claim 1 wherein R is methyl, R is methyl, R is hydrogen, R is ethyl, R is butyl and A is HENRY R. J ILES, Primary Examiner 0 G. T. TODD, Assistant Examiner US. Cl. X.R.

260239 E, 240 R, 247.5 R, 268 R, 293.56, 293.63, 296 R, 309,7, 326.85; 424244, 248, 250, 263, 267, 273, 274 

